The following studies have as their primary goal elucidation of the biosynthesis and regulation of alpha-1-antitrypsin (AAT), a glycoprotein produced in liver. The studies are to be conducted with a variety of cell types obtained from individuals with normal and deficient levels of AAT. The biochemical studies will be directed toward the identification of the molecular defect(s) associated with this inherited disease. The approaches will include studies of AAT synthesis and regulation in cultured cells and the specific posttranslational modifications of AAT following its synthesis. Since this inherited disorder has a high morbidity and significant mortality and there is little ability to intervene in its progression, reduction in the incidence of the disease is clearly desirable. Since screening and prenatal diagnosis for genetic diseases has lowered the incidence of affected cases, we propose to explore the feasibility of this approach for AAT. We have developed a radioimmunoassay (vida infra) and propose to develop new, simpler electrophoretic and immunological methods for identification of M,Z,S, and F genotypes. The feasibility of prenatal diagnosis of AAT deficiency will be investigated by direct study of amniotic cells in culture. Our approach should provide not only an understanding of the molecular basis of AAT deficiency but provide leads to its pathogenesis and genetic methods for its prevention.